There are considerable evidence that genetic predisposition to Affective Disorders strongly interacts with early attachments experience to create vulnerability to separation anxiety in childhood and to panic disorder and major depression in adulthood. The proposed studies provide the first animal model system in which these intertwining influences can be experimentally analyzed and the neurobiological mechanisms delineated for the separation cry, the first known expression of anxiety in humans as well as in young mammals. This research will continue a line of work aimed at gaining knowledge about the basic behavioral, neural and developmental processes underlying the early anxiety-like state induced by isolation of the infant rat. The PI has focused on the separation distress calling rate as this has emerged to be the most specific and consistent of this behavioral state. During the last grant period, the PI discovered a novel maternal separation effect in which brief passive contact or certain active interactions of an isolated pup with its dam, doubles or triples its subsequent rate of ultrasonic vocalization (USV). This maternal potential of the isolation response reveals the existence of a hitherto unsuspected system of affective communications between the rat mother and her pups. The proposed studies will explore the central neuromodulator pathways mediating maternal potentiation, the behavioral processes that control it, and the course of its postnatal development. In doing so the PI will test a novel hypothesis for its adaptive role, based on potential costs and benefits of high and low USV rates for isolated rat pups. In addition, during the past grant period, the PI has begun a program of selective breeding for high and for low levels of USV response to isolation. The PI will study microevolution of differences, using neuropharmacologic techniques to reveal the central neural pathways primarily involved. Finally, he will explore the developmental continuity that may exist between this infantile trait and later affective responses in weanlings, juveniles and adults.